Peroxisome proliferator-activated receptors (PPARs), like other steroid hormone nuclear receptors, are ligand-activated transcription factors. Over the past decade, extensive studies by many laboratories established a central role for the three known PPARs-alpha, gamma, and delta-in the transcriptional regulation of metabolic processes such as adipogenesis, lipid metabolism and glucose control/1-3. Indeed, synthetic PPARalpha agonists (fibrates) are in clinical use to lower triglyceride (TG) and raise high density lipoprotein (HDL) levels while synthetic PPARgamma agonists (thiazolidinediones) are employed as anti-diabetic agents. More recently, several groups, including ours, established PPAR expression in vascular and inflammatory cells (monocytes, T lymphocytes), where they regulate relevant target genes. Most of this data suggests PPAR activation limits inflammation and atherosclerosis both in vitro and in vivo. Despite intense interest in PPARs as therapeutic targets, the nature of endogenous PPAR ligands, or the pathways that might generate them have been largely undescribed. Recently, we published in vitro and in vivo evidence that lipoprotein lipase (LPL), a central enzyme in metabolism, acted on TG-rich lipoproteins to generate endogenous PPARalpha ligands. These studies also revealed a previously unappreciated anti-inflammatory role for LPL action. PPARs are known to be expressed in the skin, although little data exists regarding their role there. Based upon preliminary data, we hypothesize that LPL-treatment of TG-rich lipoproteins represent a novel anti-inflammatory mechanism in skin. Through this lipolytic/PPAR mechanism, endogenous anti-inflammatory compounds may be generated either under normal conditions or as part of a therapeutic strategy, with possible inflammatory cells. Through this pathway, entire cassettes of distal PPAR-regulated target genes might be regulated. Preliminary data supports such possibilities and argues for further studies. We outline here highly focused experiments combining examination of PPAR transcriptional regulation in vitro with studies on LPL/PPAR effects in existing mouse models of dermal inflammation in vivo. We will do so through the following specific aims (SA): SA1 Lipolytic Mechanisms of Transcriptional Regulation Through PPARs inn Keratinocytes Hypothesis: Lipolytic PPAR activation is evident in keratinocytes. Studies in this system reveals unique components of PPAR transcriptional regulation and LPL action relevant to dermal responses. GOAL: Using established models of TPA-induced ear inflammation, test the effects of LPL-mediated VLDL activation in wild-type and PPARalpha-deficient mice.